This R21 application, in response to RFA-MH-08-031, "Mechanisms of HIV Neuropathogenesis: Emerging Domestic and Global Issues," will investigate the molecular mechanisms that give rise to the waxing and waning phenotype of neurologic disease associated with HIV-1 infection of the central nervous system in the years since highly active antiretroviral therapy (HAART) has become the mainstay of therapy. Neuropsychologic and neurologic evaluations demonstrate fluctuant patterns of cognitive and motor deficits that localize in part to the corpus callosum and do not necessarily proceed in an inexorable stepwise pattern of decline that would suggest irrevocable structural damage and cell death in these pathways. Results from diffusion tensor imaging (DTI) neuroradiologic studies of patients with HIV-1 infection and neurologic disease, as well as immunocytochemical studies from human and monkey brain tissue with HIV/SIV infection demonstrate abnormalities in white matter function and axonal structure in the corpus callosum. In contrast, evidence for direct HIV-1 infection of oligodendrocytes in vivo or their cell death remains controversial. While studies have implicated HIV-1 Tat or gp120 in oligodendrocyte dysfunction, the mechanisms for this remain undefined. Here, we will focus on Tat due to its unique ability to modulate synaptic transmission, as well as initiate recruitment and activation of mononuclear cells in the CNS to amplify its neurotoxicity. As a first step in understanding fluctuant changes in neurologic status that are referable in part to damage to the corpus callosum, we will model dysfunction of the corpus callosum in vivo by investigating how HIV-1 Tat may directly or indirectly damage oligodendrocyte precursor cells that are in synaptic communication with axons, and impair axonal conduction in the callosum. This type of synapse is characterized by activity-dependent vesicular release of the excitatory neurotransmitter glutamate from axons and can induce ionotropic currents in [post-synaptic] oligodendrocyte progenitor cells (OPCs) that express the membrane proteoglycan NG2 (NG2+), and ultimately differentiate into oligodendrocytes. We further hypothesize that Tat can recruit infiltrating perivascular macrophages to exacerbate damage to OPC pools, ultimately affecting the ability of OPC to contribute to the population of mature oligodendrocytes that maintains normal callosal structure and function. To test these hypotheses, in aim 1, we will investigate how HIV-1 Tat and infiltrating perivascular macrophages can affect the life cycle of OPC pools and callosal structure and in aim 2, we will investigate how HIV-1 Tat can alter communication between callosal axons and OPCs and investigate whether this in turn impairs axonal conduction in intact brain slices. Data from these experiments will further our understanding of whether damage to components of the axon-OPC synapse contributes to HIV-1 associated neurologic disease and may represent a previously unidentified therapeutic target.